Project Summary It is widely-accepted by both clinicians and basic scientists that stress can trigger and worsen seizures in animal models and in patients with epilepsy through the actions of stress mediators. The body's physiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. The majority of studies investigating the relationship between the HPA axis and epilepsy focus on the role of stress and the proconvulsant actions of corticosterone (cortisol in humans) and corticotropin-releasing hormone (CRH). Interestingly, our lab recently demonstrated that seizures themselves activate the HPA axis, forcing us to reevaluate the role of the HPA axis in epilepsy. These findings suggest that seizure-induced activation of the HPA axis may directly contribute to changes in seizure susceptibility. Further, hyperexcitability of the HPA axis is a hallmark feature of depression, implicating seizure-induced activation of the HPA axis in the comorbidity of depression and epilepsy. The overarching objective of the current study is to investigate the pathophysiological consequences of this seizure-induced activation of the HPA axis, investigating the impact on the process of epileptogenesis (Specific Aim 1), seizure activity in chronically epileptic mice (Specific Aim 2), and the role in the comorbid depression (Specific Aim 3). These Aims will determine whether seizure-induced activation of the HPA axis is culpable in worsening seizure activity, associated pathology, and depression-like behaviors in chronically epileptic mice.